Phosphoproteomics Illuminates Opioid Actions

Opioids are widely used analgesic medications with a high potential for tolerance and dependence and represent a frequent cause of death due to overdose. Opioids mediate their actions via a family of opioid G protein coupled receptors. Elucidating the biochemical mechanism(s) responsible for both the therapeutic and deleterious side effects of opioids could provide a biochemical roadmap for selectively targeting therapeutic signaling pathways. Here we provide a perspective on emerging findings, which illuminate these signaling pathways via unbiased and quantitative phosphoproteomic analysis. What emerged from these studies is the discovery that certain deleterious actions mediated by the κ opioid receptors appear due to specific activation of mTOR pathways. The findings imply that designing drugs, which bypass mTOR signaling, could yield safer and more effective analgesics.